This proposal requests the renewal of our major source of long-standing funding for investigating the epigenetics of pancreatic diseases. Our studies will directly extend our knowledge on common diseases, such as chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC), both painful and incurable disorders of the exocrine pancreas for which effective treatments remain to be discovered. Our OVERALL OBJECTIVE is to unravel novel epigenetic mechanisms that extend oncogenic growth signals downstream from KRAS during initiation and pancreatitis-associated cancer promotion. Our preliminary data identify HP1? as a pro-oncogenic epigenetic regulator of gene activation and growth, which is overexpressed in human pancreatic cancer as well as in animal models of pancreatic carcinogenesis. We provide solid evidence that this increased level of HP1? enhances the malignant effects of the KRAS oncogene. Our CENTRAL HYPOTHESIS is that the epigenetic regulator, HP1, works downstream from KRAS to promote pancreatic cell growth by regulating the expression of proliferative gene networks induced by this oncogene. Our AIMS will test the following hypotheses: Aim 1: HP1? participates in a membrane-to-nucleus gene regulatory pathway that enhances the ability of KRAS to mediate neoplastic transformation and tumorigenesis; Aim 2: HP1? works downstream of KRAS to regulate growth-promoting gene networks; and Aim 3: HP1? inhibition ameliorates KrasG12D-mediated PDAC initiation and promotion after pancreatitis. Our design proposes molecular, cellular, and whole organism experiments using state-of-the-art methodologies. Accordingly our laboratory has developed the appropriate conceptual framework, reagents, trained personnel and has established productive collaborations. The innovative design of this proposal seeks to maximize the yield of mechanistic and rapidly translatable knowledge in this underepresented yet extremely the new promising area of epigenetics in pancreatic diseases. As new drugs targeting both the KRAS and HP1 pathways are being tested in clinical trials, this proposal builds the rationale for applying these tools to the management of patients affected with deadly pancreatic diseases, thereby bearing significant biomedical relevance.